scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Abstract Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

scholarly journals Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5647-5647
Author(s):  
Yuan Li ◽  
Qing Ya Wang ◽  
Ze Yin Liang ◽  
Yue Yin ◽  
Wei Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Relapse Time ◽  
Risk Patients ◽  
Grade Ii ◽  
Acute Graft

Objective: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate- and high-risk patients with MDS or AML. Methods:Retrospective analysis of data pertaining to 76 intermediate and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabine containing conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine. Results: Overa median follow up of 40 months(range, 1 to 155), the incidence of grade II to IV acute graft versus host disease was 12.5% in the Decitabine group and 41.7% in the non-Decitabine group (P=0.003). On multivariate analysis, Decitabine containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.275, 95% confidence interval 0.098-0.770,P=0.014). Incidence of respiratory infection in the Decitabine and non Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.837, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2 to 12) versus 3 months (range, 2 to 4), P=0.171]. Decitabine containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the between-group difference was not statistically significant (P=0.085). Conclusions: Inclusionof Decitabine in the conditioning regimen for allo-HSCT in intermediate- and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prevention of graft-versus-host disease in high risk patients by depletion of CD4+ and reduction of CD8+ lymphocytes in the marrow graft

1999 ◽  
Vol 23 (5) ◽  
pp. 443-450 ◽  
Author(s):  
C Herrera ◽  
A Torres ◽  
J M García-Castellano ◽  
J Roman ◽  
C Martin ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Marrow Graft ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Grade 2–4 Acute Graft-Versus-Host Disease and Extensive Chronic Graft-Versus-Host Disease Are Associated with Significantly Decreased Survival Following Reduced Intensity Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1246-1246
Author(s):  
Geoffrey W. Chan ◽  
Andreas K. Klein ◽  
Kellie A. Sprague ◽  
Kenneth B. Miller ◽  
Francine M. Foss
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients ◽  
Grade 3 ◽  
Reduced Intensity

Abstract Grade 2–4 acute graft versus host disease (aGVHD) is associated with decreased overall survival following conventional allogeneic stem cell transplantation but its impact on reduced intensity transplantation remains controversial. We evaluated the impact of grade 2–4 aGVHD on survival in a retrospective review of 112 high-risk patients, median age 50 (range 18 to 70), with AML (n=29), MDS (n=19), CML (n=9), CLL (n=5), ALL (n=3), HD (n=10), NHL (n=16), MM (n=9), MMM (n=7), PNH (n=2), or renal cell carcinoma (n=3), who underwent a reduced intensity preparative regimen of extracorporeal photopheresis day −7, −6, pentostatin 8mg/m2 by continuous intravenous infusion day −5 thru −4, and total body irradiation in three 200cGy fractions day −3, −2, followed by allogeneic bone marrow stem cell infusion from a 6/6 HLA matched related (n=70), 5/6 HLA matched related (n=10), or matched unrelated (n=32) donor. All patients were high-risk, including 30 patients with a prior autologous stem cell transplant and 5 patients with a prior allogeneic stem cell transplant. Full donor chimerism at the time of neutrophil engraftment was achieved in 89% of patients. The median time to neutrophil and platelet engraftment were 19 and 21 days respectively. Day 100 transplant related mortality(TRM) was 20%. Disease relapse occurred in 22% of patients. Grade 0 or 1 aGVHD occurred in 27 patients (27%) and 54 patients (54%) respectively. Grade 2, 3 or 4 aGVHD occurred in 7 patients (7%), 6 patients (6%), and 7 patients (7%) respectively. The one-year overall survival (OS) by aGVHD grade was 70% for grade 0, 69% for grade 1, 29% for grade 2, 17% for grade 3, and 0% for grade 4. Grade 2–4 aGVHD was associated with a significantly increased day 100 TRM (37% vs 14%: p=0.03), decreased median failure-free survival (5 months vs 35 months: p=0.001), and decreased median OS (5 months vs “not reached”: p=0.001). The decrease in median OS among patients with grade 2–4 aGVHD was significant among matched related donor transplants (5 months vs “not reached”: p=0.002) and among mismatched related or matched unrelated donor transplants (6 months vs 35 months: p=0.0004). There was no significant difference in median OS between patients with grade 2 aGVHD and patients with grade 3–4 aGVHD (6 months vs 3 months: p=0.24). Patients with limited or no chronic GVHD (cGVHD) had similar one-year OS (90% vs 79%) but patients who developed extensive chronic GVHD had a significantly worse median OS (56% vs “not reached”: p=0.001). In conclusion, high-risk patients who undergo reduced intensity transplantation and develop grade 2–4 aGVHD or extensive cGVHD have a significantly decreased overall survival. Patients with grade 2 aGVHD have similarly poor OS as patients with grade 3–4 aGVHD. High-risk patients tolerate GVHD poorly with a significantly decreased overall survival. To improve survival, reduced intensity transplantation regimens that decrease the incidence of grade 2–4 aGVHD or extensive cGVHD need to be developed. Figure Figure

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin–based reduced-intensity preparative regimen

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 470-476 ◽  
Author(s):  
Mohamad Mohty ◽  
Jacques-Olivier Bay ◽  
Catherine Faucher ◽  
Bachra Choufi ◽  
Karin Bilger ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients ◽  
Reduced Intensity

AbstractReduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P = .0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P = .0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P = .02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.

DNA Typing for HLA-A and HLA-B Identifies Disparities Between Patients and Unrelated Donors Matched by HLA-A and HLA-B Serology and HLA-DRB1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 399-409 ◽  
Author(s):  
Vinod K. Prasad ◽  
Nancy A. Kernan ◽  
Glenn Heller ◽  
Richard J. O’Reilly ◽  
Soo Young Yang
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Dna Typing ◽  
Outcome Studies ◽  
Cancer Center ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Variation ◽  
Unrelated Donors

Abstract High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P< .01) and 4/6 (P < .01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67.4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P = .01). The level of allelic disparity was lower (P < .01 for 6/6; P = .02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.

scholarly journals Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1756-1764 ◽  
Author(s):  
Yukimi Sakoda ◽  
Daigo Hashimoto ◽  
Shoji Asakura ◽  
Kengo Takeuchi ◽  
Mine Harada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

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